JPS6013028B2 - Trifluoromethyl-substituted compounds with antidepressant activity - Google Patents
Trifluoromethyl-substituted compounds with antidepressant activityInfo
- Publication number
- JPS6013028B2 JPS6013028B2 JP51105451A JP10545176A JPS6013028B2 JP S6013028 B2 JPS6013028 B2 JP S6013028B2 JP 51105451 A JP51105451 A JP 51105451A JP 10545176 A JP10545176 A JP 10545176A JP S6013028 B2 JPS6013028 B2 JP S6013028B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- trifluoromethyl
- compound
- pharmaceutically acceptable
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 title claims description 39
- 230000001430 anti-depressive effect Effects 0.000 title description 4
- 230000000694 effects Effects 0.000 title description 4
- 239000000935 antidepressant agent Substances 0.000 title description 2
- 229940005513 antidepressants Drugs 0.000 title description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- -1 p-toluenesulfonyloxy Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 9
- 229960004801 imipramine Drugs 0.000 description 8
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003710 aryl alkyl group Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 229910052801 chlorine Inorganic materials 0.000 description 2
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- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- XGASTRVQNVVYIZ-UHFFFAOYSA-N 1-(chloromethyl)-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(CCl)=C1 XGASTRVQNVVYIZ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920000018 Callose Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- IUWXTPUCYFQATQ-UHFFFAOYSA-N [2-methyl-1-[3-(trifluoromethyl)phenyl]propan-2-yl] 2-aminopropanoate Chemical compound CC(N)C(=O)OC(C)(C)CC1=CC=CC(C(F)(F)F)=C1 IUWXTPUCYFQATQ-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
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- 125000001246 bromo group Chemical group Br* 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 231100000259 cardiotoxicity Toxicity 0.000 description 1
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- 229960003920 cocaine Drugs 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical class CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Emergency Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新規なアミノ酸トリフルオロメチル置換ァラル
キルェステルおよびその製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel trifluoromethyl-substituted aralkyl esters of amino acids and processes for their production.
本発明はさらに前記化合物の薬理学的使用方法および前
記化合物を含有する製剤に関する。本発明の目的は中枢
神経系に対する作用特に抗抑うつ活性を有し、かつ副作
用が軽減され、この分野において現在使用されている医
薬と比較してより高い効果を有する化合物を提供するこ
とにある。The invention further relates to methods of pharmacological use of said compounds and formulations containing said compounds. The object of the present invention is to provide a compound that has an effect on the central nervous system, particularly antidepressant activity, has reduced side effects, and is more effective than drugs currently used in this field.
さらに本発明の目的は活性成分として本発明による化合
物を含有する製剤を提供することにある。Furthermore, it is an object of the invention to provide preparations containing a compound according to the invention as active ingredient.
本発明のさらに他の目的は抑うつ症の袷療方法を提供す
ることにある。Still another object of the present invention is to provide a method for treating depression.
現在抑うつ症の抑制に最も広く使用されている化合物は
式のィミプラミン(商標名トフラニール)である。The compound currently most widely used to control depression is the formula imipramine (trade name Tofranil).
この化合物は気分を高揚しかつ精神運動性を活性化する
が数種の欠点を有する。すなわち、ィミプラミンは抗副
交感神経性であって、口潟、振顕、瀕派および発汗のよ
うな抗劉交感神経性症候症の原因となる。比較的高い用
量においては重症の心臓不整脈を起こし、標準用量では
心不全の患者に有毒な交互作用を誘発する。さらに、ィ
ミプラミンによる治療の欠点は抗抑うつ効果の発現が遅
いことであり、該効果は処置後約3週間ではじめて認め
られる。ィミプラミンは中枢神経系の伝達物質の作用に
対して影響を及ぼすことが知られている。Although this compound is mood elevating and psychomotor activating, it has several drawbacks. That is, imipramine is anti-parasympathetic and causes anti-parasympathetic symptoms such as lagoon, tremors, diaphoresis, and sweating. At relatively high doses it causes severe cardiac arrhythmias, and at standard doses it induces toxic interactions in patients with heart failure. Furthermore, a drawback of treatment with imipramine is the slow onset of the antidepressant effect, which is only noticed about 3 weeks after treatment. Imipramine is known to influence the actions of transmitters in the central nervous system.
さらに詳しくは、ィミプラミンはノルアドレナリン(N
A)および5−ヒドロキシトリプタミン(5−HT)の
再吸収機構を抑制する。抗抑うつ作用の気分高揚作用の
部分は主として5一HT吸収の抑制に関連することが予
想される。本発明によれば、アミノ酸のトリフルオロメ
チル置換アラルキルェステルとして表現されることので
きるある種の新規な化合物が5−ヒドロキシトリブタミ
ンの中枢神経単位の吸収の選択的抑制に使用可能である
ことが見出された。More specifically, imipramine is noradrenaline (N
A) and inhibits the reabsorption mechanism of 5-hydroxytryptamine (5-HT). It is expected that the mood-elevating part of the antidepressant effect is primarily related to the suppression of 5-HT absorption. According to the present invention, certain novel compounds, which can be described as trifluoromethyl-substituted aralkyl esters of amino acids, can be used for the selective inhibition of central nervous system absorption of 5-hydroxytributamine. was discovered.
さらに前記新規化合物の心臓毒性はィミプラミンよりも
かなり弱い。本発明による新規な化合物は一般式
(式中茎Roはトリフルオロメチルである)およびその
製薬上許容し得る酸付加塩によってあらわされることが
できる。Furthermore, the cardiotoxicity of the new compound is considerably less than that of imipramine. The novel compounds according to the invention can be represented by the general formula (wherein Ro is trifluoromethyl) and its pharmaceutically acceptable acid addition salts.
以下の2種の化合物が本発明による好適な化合物の例と
してあげられる。The following two compounds may be mentioned as examples of suitable compounds according to the invention.
2ーアミノプロパン酸1−(3ートリフルオロメチルフ
エニル)一2−メチル一2ープロピルエステ′レ2−ア
ミノプロパン酸1−(4−トリフルオロメチルフエニル
)一2ーメチル−2ープロピルエステル。2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-12-methyl-2-propyl ester 2-aminopropanoic acid 1-(4-trifluoromethylphenyl)-12-methyl-2-propyl ester.
本発明の前記化合物は一般式 (式中Roはトリフルオ。The compounds of the present invention have the general formula (In the formula, Ro is trifluoro.
メチルでありXは塩素または臭素のようなハロゲンある
いはp−トルェンスルホニルオキシである)の化合物を
アンモニアと反応させることによって製造され得る。前
記一般式0の中間体は新規化合物であり、本発明のさら
に他の面を構成する。この化合物は一般式(式中Roは
前記の意味をあらわす)のアルコ−ルを式Y−CO−C
H(CH3)×(式中×は前記の意味をあらわしYは臭
素または塩素である)の化合物と反応させることによっ
て製造することができる。methyl and X is a halogen such as chlorine or bromine or p-toluenesulfonyloxy) with ammonia. The intermediate of general formula 0 is a novel compound and constitutes yet another aspect of the present invention. This compound converts the alcohol of the general formula (wherein Ro represents the above meaning) into the alcohol of the formula Y-CO-C
It can be produced by reacting with a compound of H(CH3)× (in the formula, x represents the above meaning and Y is bromine or chlorine).
前記一般式0とアンモニアとの反応はそれらの反応成分
を溶解し得る不活性有機溶媒中で実施されるのが好まし
い。The reaction of the general formula 0 with ammonia is preferably carried out in an inert organic solvent capable of dissolving the reaction components.
任意適当な反応圧および反応温度を採用することができ
る。好適には該反応は大気圧下または過大気圧下、一1
0℃ないし+100℃、好ましくは0〜30午0の温度
において実施される。本発明の新規化合物は治療上、合
成の際通常の場合に得られる(十)形および(一)形の
ラセミ混合物として使用され得る。Any suitable reaction pressure and reaction temperature can be employed. Preferably the reaction is carried out under atmospheric pressure or superatmospheric pressure.
It is carried out at a temperature of 0° C. to +100° C., preferably 0 to 30 am. The novel compounds of the invention can be used therapeutically as a racemic mixture of the (decade) and (mono)forms obtained in the usual case during synthesis.
前記混合物はさらにそれ自体既知の方法によって相当す
る光学的に活性な変態に分割され、これら変態もまた同
様に治療に使用され得る。所望に応じて、前記光学的活
性変態は例えば前述の一般式0の光学的活性化合物を経
由して直接合成法によって製造されることもできる。臨
床上、本発明の前記化合物は通常経口的、経直腸的ある
いは注射により、遊離塩基または、例えば塩酸塩、臭化
水素酸塩、乳酸塩、酢酸塩、りん酸塩、硫酸塩、スルフ
アミン酸塩、〈えん駿塩、酒石酸塩、しゆう酸塩等のよ
うな製薬上許容し得る非毒性酸付加塩のいずれかの形態
の清性成分を製薬上許容し得る担体と併用してなる製剤
の形で投与される。Said mixtures can be further divided into the corresponding optically active modifications by methods known per se, and these modifications can likewise be used therapeutically. If desired, said optically active modifications can also be prepared by direct synthetic methods, for example via the optically active compounds of general formula 0 described above. Clinically, the compounds of the invention are usually administered orally, rectally or by injection in the free base or in the form of, for example, the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate salt. , (for formulations comprising a cleansing ingredient in the form of any pharmaceutically acceptable non-toxic acid addition salt, such as enesulfate, tartrate, oxalate, etc., in combination with a pharmaceutically acceptable carrier). administered in the form of
従って、本発明の前記新規化合物に関する用語は一般的
表現あるいは特定的表現のいずれであっても、例えば特
定の実施例において、該用語が用いられている文の前後
関係が広義の概念に不一致でなければ、遊離ァミン塩基
および該遊離塩基の酸付加塩の両方を包含することを意
図するものである。前述の担体は固体、半固体または液
体希釈剤あるいはカプセルであり得る。活性物質0.1
〜95重量%を含有する前記製剤は本発明のさらに他の
面を機成する。通常、活性物質は注射用製剤の0.5〜
2の重量%を構成し、経口投与用として適する製剤の2
〜5の重量%を構成する。本発明の化合物を経口適用の
ための用量単位形態で含有する製剤を製造するためには
、選択された化合物を固体の粉体状迫体、例えば乳糖、
サ、ッカロース、ソルビット、マンニツト、馬鈴薯殿粉
、とうもろこし殿粉またはアミロベクチンのような殿粉
、セルロース誘導体、ゼラチンまたはポリビニルピロリ
ドンのような結合剤、ステアリン酸マグネシウム、ステ
アリン酸カルシウム、ポリエチレングリコールワックス
のような潤滑剤等と混合し、次に圧縮して錠剤を生成さ
れ得る。Therefore, regardless of whether the term relating to the novel compound of the present invention is a general expression or a specific expression, for example, in a particular example, the context of the sentence in which the term is used is inconsistent with the broader concept. If not, it is intended to include both the free amine base and the acid addition salt of the free base. The aforementioned carrier can be a solid, semi-solid or liquid diluent or a capsule. Active substance 0.1
Said formulations containing ˜95% by weight constitute yet another aspect of the invention. Usually, the active substance is 0.5 to
2 of the formulation and suitable for oral administration.
~5% by weight. In order to prepare formulations containing the compounds of the invention in dosage unit form for oral application, the selected compounds may be prepared in a solid powder form, e.g. lactose,
Starches such as sugar, callose, sorbitol, mannite, potato starch, corn starch or amylobectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol wax. tablets, etc., and then compressed to form tablets.
被覆錠剤が要求される場合には、前述のようにして製造
された錠剤の心を、例えばアラビアゴム、ゼラチン、タ
ルク、二酸化チタン等を含有し得る濃縮糖溶液で被覆し
得る。別法としては、前記錠剤を易揮発性有機溶媒また
は有機溶媒混合物中に溶解されたラッカーで被覆するこ
ともできる。前記被覆剤には異なった活性物質を含有す
る錠剤あるいは異なった量の活性化合物を含有する錠剤
を容易に区別するために染料を添加し得る。ゼラチンお
よび例えばグリセロールからなる軟質ゼラチンカプセル
剤(真珠の形をした密封カプセル剤を製造するためには
前記活性物質を植物油と混合し得る。If coated tablets are desired, the tablet cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablets can be coated with a lacquer dissolved in a readily volatile organic solvent or organic solvent mixture. Dyes may be added to the coating in order to easily distinguish between tablets containing different active substances or different amounts of active compound. Soft gelatin capsules consisting of gelatin and, for example, glycerol (to produce sealed pearl-shaped capsules, the active substance can be mixed with vegetable oil).
硬質ゼラチンカプセル剤は前記活性物質の額粒を乳糖、
サツカロース、ソルビット、マンニツト、殿粉(例えば
、馬鈴薯殿粉、とうもろこし殿粉またはアミロベクチン
)、セルロ−ス誘導体あるいはゼラチンのような固体の
粉体状担体との組み合せで含有し得る。経直腸的に適用
される用量単位形は中性脂肪塩基と混和した活性物質か
らなる坐薬、あるいは植物油またはパラフィン油と混和
した活性物質からなるゼラチン直腸カプセルの形で製造
され得る。Hard gelatin capsules contain granules of the active substance such as lactose,
It may be included in combination with a solid powder carrier such as sutucarose, sorbitol, mannite, starch (eg potato starch, corn starch or amylobectin), cellulose derivatives or gelatin. Dosage unit forms for rectal application can be prepared in the form of suppositories consisting of the active substance admixed with neutral fatty bases or gelatin rectal capsules consisting of the active substance admixed with vegetable or paraffin oil.
経口適用のための液体製剤はシロップまたは懸濁液の形
、例えば、前記活性物質約0.2重量%ないし約2の重
量%を含有し、残部が糖ならびにエタノール、水、グリ
セロールおよびプロピレングリコールの混合物である溶
液であってもよい。場合により、前述の液体製剤は着色
剤、香味剤、サッカリンおよび濃厚化剤としてのカルボ
キシメチルセルロースを含有し得る。注射により腸管外
的に適用される溶液は前記活性物質の製薬上許容し得る
水落性塩を好ましくは約0.5重量%ないし約1の重量
%の濃度で含有する水性溶液の形で製造され得る。Liquid preparations for oral application are in the form of syrups or suspensions, for example containing from about 0.2% to about 2% by weight of said active substance, the balance being sugars and ethanol, water, glycerol and propylene glycol. The solution may be a mixture. Optionally, the aforementioned liquid formulations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent. Solutions to be applied parenterally by injection are prepared in the form of an aqueous solution containing a pharmaceutically acceptable water-soluble salt of the active substance, preferably in a concentration of about 0.5% to about 1% by weight. obtain.
これら溶液は安定化剤および(または)緩衝剤をも含有
し、有利には各種の用量単位のアンプルとして供給され
得る。治療的処置における本発明の化合物の適当な1日
用量は経口投与に関しては100〜500奴であり「腸
管外投与に関しては20〜100の9である。These solutions also contain stabilizers and/or buffers and can advantageously be supplied as ampoules in various dosage units. Suitable daily doses of the compounds of the invention in therapeutic treatment are from 100 to 500 g for oral administration and from 20 to 100 g for parenteral administration.
本発明の好適な化合物は式を有する。Preferred compounds of the invention have the formula:
この化合物はその塩酸塩の形で製造かつ使用されるのが
好ましい。以下の例において本発明による化合物の製造
を例示する。Preferably, this compound is prepared and used in the form of its hydrochloride. The following examples illustrate the preparation of compounds according to the invention.
2ーアミノプロパン酸1−(3ートリフルオロメチルフ
エニル)−2ーメチル−2−プロピルエステルの製造エ
ーテル(130M)中の3ートリフルオロメチルベンジ
ルクロライド(25.0夕、0.128モル)の溶液を
50分間かけて縄梓器および還流冷却器を備えた3類乾
燥フラスコ中のマグネシウム(3.11夕、0.128
モル)に滴下した。Preparation of 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester Solution of 3-trifluoromethylbenzyl chloride (25.0 m, 0.128 mol) in ether (130 M) Magnesium (3.11 evening, 0.128
mol).
自然発生的還流をさらに30分間継続させた。前記溶液
を冷却しアセトン(7.45夕、0.128モル)を滴
下し(8分間)、該溶液を3時間還流加熱した。冷却後
、以上の反応混合物を氷(100の【)および濃塩酸(
11の‘)上に注加した。各相に分離した。有機相を水
洗、乾燥(Na2SQ)そして真空蒸発させた。残留油
の分留により1−(3ートリフルオロメチルフェニル)
一2−メチル一2ーブロパノールが生成した。(b.p
.63〜64℃/1.0側Hg、m.p.55〜56℃
石油エーテルから再結晶)収率73%(20.3夕)。
上記の置換プロパノール(15.0夕、0.069モル
)をジメチルアニリン(9.32夕、0.077モル)
およびジクロロメタン(50の【)と混合した。得られ
た溶液を冷却し、2−ブロモプロピオニルフロマィド(
22.2夕、0.103モル)を1時間で滴下した。室
温における鷹拝を一夜継続した。以上の反応混合物に水
(200の‘)を添加して各相を分離させた。が‐炭酸
水素ナトリウム溶液で洗浄後、有機相を真空蒸発させた
。残留油を0.1N一硫酸および水で3回洗浄したエー
テル(200の【)で希釈した。前記エーテル溶液を乾
燥(Na2S04)し真空蒸発させた。前記残留細から
2−プロモープロパン酸1−(3−トリフルオロメチル
フエニル)一2ーメチル−2−プロピルエステル(2.
10夕、87%)が得られた。上記のブロモェステル(
21.0夕、0.059モル)をエタノール(600奴
)中に溶解させ、0℃に冷却した。Spontaneous reflux was continued for an additional 30 minutes. The solution was cooled, acetone (7.45 min, 0.128 mol) was added dropwise (8 minutes), and the solution was heated to reflux for 3 hours. After cooling, the above reaction mixture was poured into ice (100%) and concentrated hydrochloric acid (
11'). Separated into each phase. The organic phase was washed with water, dried (Na2SQ) and evaporated in vacuo. 1-(3-trifluoromethylphenyl) is produced by fractional distillation of the residual oil.
12-methyl-12-propanol was produced. (b.p.
.. 63-64°C/1.0 side Hg, m. p. 55-56℃
Recrystallization from petroleum ether) Yield 73% (20.3 evenings).
The above substituted propanol (15.0 min, 0.069 mol) was mixed with dimethylaniline (9.32 min, 0.077 mol).
and dichloromethane (50%). The resulting solution was cooled and 2-bromopropionyl furomide (
On the evening of 22.2, 0.103 mol) was added dropwise over 1 hour. Hawk worship was continued overnight at room temperature. Water (200') was added to the above reaction mixture to separate the phases. After washing with sodium bicarbonate solution, the organic phase was evaporated in vacuo. The residual oil was diluted with ether (200) washed three times with 0.1N monosulfuric acid and water. The ether solution was dried (Na2S04) and evaporated in vacuo. From the residual fines, 2-promopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester (2.
10 days later, 87%) was obtained. The above bromoester (
0.059 mol) was dissolved in ethanol (600 mol) and cooled to 0°C.
この溶液をアンモニアで飽和させた(4時間)。室温に
おいて縄梓を5幼時間継続し、この間アンモニア飽和を
さらに2回行なった。前記の溶媒を真空除去し、残留油
を0.が−塩酸に溶解させエーテルで洗浄した。酸性相
を州‐水酸化ナトリウムの添加によりpH9.0のアル
カリ性にした。アルカリ性相のエーテル抽出を2回行な
い、有機層、乾燥(Na2S04)および真空蒸発させ
た。塩基性油状残留物から塩酸塩が製造された。アセト
ンからの再結晶により2−アミノプロパン酸1一(3ー
トリフルオロメチルフエニル)一2ーメチルー2−プロ
ピルェステル塩酸塩(m.p.140〜141℃、12
.70夕、収率66%)が得られた。薬理学的方法A
生化学的試験1 14C−5−HTおよびトリチウム標
識ノルアドレナリンの試験管内および生体内における吸
収抑制ヨーロピアン・ジヤーナル・オプ・フアーマコロ
ジー、17(1972)、第107〜112頁に記載の
方法(Ross、Ren打および0gにn著)に従って
試験する。This solution was saturated with ammonia (4 hours). Roping was continued for 5 hours at room temperature, during which time ammonia saturation was carried out twice more. The solvent was removed in vacuo and the residual oil was reduced to 0. was dissolved in hydrochloric acid and washed with ether. The acidic phase was made alkaline to pH 9.0 by addition of sodium hydroxide. Ether extraction of the alkaline phase was carried out twice and the organic layer was dried (Na2S04) and evaporated in vacuo. The hydrochloride salt was prepared from the basic oily residue. Recrystallization from acetone yielded 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propylester hydrochloride (m.p. 140-141°C, 12
.. 70 days, yield 66%) was obtained. Pharmacological method A
Biochemical test 1 Inhibition of absorption of 14C-5-HT and tritiated noradrenaline in vitro and in vivo The method described in European Journal of Pharmacology, 17 (1972), pp. 107-112 (Ross, Tested according to Ren et al. and 0 g.
試験管内に添加されるかあるいはマウスに対して生体内
に投与されるイミブラミン型の3環性抗抑うつ剤は試験
管内において14C−5−HTおよび3H−NAの吸収
を低下させる。試験管内実験において、各種の異なる濃
度の供試化合物をインキュベーション媒質に添加した。
生体内実験においては、各種の異なる用量の供試医薬を
試験動物をと殺する30分前に腹腔内に投与した。以上
の2種のタイプの実験においてインキュベーション方法
は同一であり、それぞれの中脳を摘出してスライスし、
クレプス・ヘンセラィト緩衝液(pH7.4)2の【中
、前記脳切片100雌あたり、14C−5−HTO.2
ナノモル、3H−NAO.2ナノモルおよびグルコース
11マイクロモルからなる混合物中でインキュベートし
た。インキュベーション時間は5分間であった。脳切片
中に吸収された前記放射性アミンをトルェン中の0.州
第4級水酸化アンモニウムの溶液であるソルェン−35
0(Soluene−350:商標名Packard)
に溶解させ、その量を液体シンチレーションにより二重
標識法に従って測定した。活性吸収の50%低下(ED
5o)を生ずる前記濃度または用量を用量一応答曲線か
ら図式的に測定した。活性吸収は放射性吸収の高濃度の
コカインによって抑制される部分として定義される。各
用量はすべて少なくとも4匹の試験動物に投与された。
以上の試験において得られた結果を後記表に記載するが
、表中コード番号CEA820は2−アミノプロパン酸
1−(3ートリフルオロメチルフェニル)一2−メチル
−2−プロピルェステル塩酸塩すなわち本発明による化
合物を意味する。Tricyclic antidepressants of the imibramine type added in vitro or administered in vivo to mice reduce the absorption of 14C-5-HT and 3H-NA in vitro. In in vitro experiments, different concentrations of test compounds were added to the incubation medium.
In the in vivo experiments, different doses of the test drug were administered intraperitoneally 30 minutes before the test animals were sacrificed. The incubation method was the same in the above two types of experiments, and each midbrain was removed and sliced.
14C-5-HTO.14C-5-HTO per 100 females in Kreps-Henseleit buffer (pH 7.4). 2
Nanomol, 3H-NAO. It was incubated in a mixture consisting of 2 nanomoles and 11 micromoles of glucose. Incubation time was 5 minutes. The radioactive amine absorbed into the brain slices was dissolved in toluene at 0.0%. Sollen-35, a solution of quaternary ammonium hydroxide
0 (Soluene-350: Trade name Packard)
The amount was determined by liquid scintillation according to the double labeling method. 50% reduction in active absorption (ED
The concentrations or doses resulting in 5o) were determined graphically from dose-response curves. Active absorption is defined as the portion of radioactive absorption that is suppressed by high concentrations of cocaine. All doses were administered to at least 4 test animals.
The results obtained in the above tests are listed in the table below. In the table, the code number CEA820 is 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propylester hydrochloride. means a compound according to the invention.
この化合物をマウスの腹腔内に投与した場合のLD劫は
477ムmol/k9であった。表
イミプラミン 0.1 0.06 2 4
61)5−HT=5−ヒドロキシトリプタミ
ン1×10−7M2)NA=1ーノルアドレナリン1×
10一7M薬理学的試験において得られた結果の評価本
発明の化合物は試験管内および生体内で脳切片の5−ヒ
ドロキシトリブタミン吸収を遮断するがノルアドレナリ
ンの吸収は抑制しない。When this compound was administered intraperitoneally to mice, the LD value was 477 mmol/k9. Table Imipramine 0.1 0.06 2 4
61) 5-HT = 5-hydroxytryptamine 1 x 10-7 M2) NA = 1 noradrenaline 1 x
Evaluation of the Results Obtained in the 1017M Pharmacological Test The compounds of the invention block 5-hydroxytributamine absorption in brain slices in vitro and in vivo, but do not inhibit the absorption of noradrenaline.
以上の結果は前記の新規化合物が5ーヒドロキシトリブ
タミンの吸収抑制においてィミプラミンよりもはるかに
選択的であることを示す。These results indicate that the new compound is much more selective than imipramine in inhibiting the absorption of 5-hydroxytributamine.
製剤組成物 以下の例は本発明による製剤組成物の製造を例示する。Pharmaceutical composition The following examples illustrate the production of pharmaceutical compositions according to the invention.
錠剤の製造に際しては次の組成物が調製された。a 2
ーアミノブロバン酸1−(
3ートリフルオロメチルフヱニル
)−2−メチル−2ープロピルエ
ステル塩酸塩(GEA820) 50タ乳 糖
85夕馬鈴薯殿粉
40夕ポリビニルピロリドン 5
タ
セルロース・アヴイセル 18タ
ステアリン酸マグネシウム 2#
b 2ーアミノプロパン酸1一(
3ートリフルオロメチルフヱニル
)−2ーメチルー2−プロピルエ
ステル塩酸塩(GEA820) 100タ乳 糖
90夕馬鈴薯殿粉
50夕
ポリビニルピロリドン 5タ
セルロース・アヴイセル 23タステアリン
酸マグネシウム 2タ以上の組成物a)およびb
)からそれぞれ活性物質50雌および100の9を含有
する100の固の錠剤が製造された。The following composition was prepared for tablet production. a2
-Aminobrovanic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester hydrochloride (GEA820) 50 lactose
85 Yu potato powder
40 Polyvinylpyrrolidone 5
Tacellulose Avicel 18 Magnesium Tastearate 2# b 2-aminopropanoic acid 1-(3-trifluoromethylphenyl)-2-methyl-2-propyl ester hydrochloride (GEA820) 100 Ta Lactose
90 Yu potato powder
50 Polyvinylpyrrolidone 5 Cellulose Avicel 23 Magnesium stearate Compositions of 2 or more a) and b
) were prepared from 100 hard tablets each containing 50 female and 9 of 100 active substances.
Claims (1)
れる化合物およびその製薬上許容し得る酸付加塩。 2 R^0がフエニル環のメタ位に存在するトリフルオ
ロメチルである前記第1項の化合物およびその製薬上許
容し得る酸付加塩。 3 R^0がフエニル環のパラ位に存在するトリフルオ
ロメチルである前記第1項の化合物およびその製薬上許
容し得る酸付加塩。 4 光学的に純粋な異性体形の前記第1〜3項のいずれ
か一つに記載の化合物。 5 一般式 ▲数式、化学式、表等があります▼ (式中R^0はトリフルオロメチルであり、Xはハロゲ
ンおよびp−トルエンスルホニルオキシから選択される
)であらわされる化合物をアンモニアと反応させること
を特徴とする、一般式 ▲数式、化学式、表等があります▼ (式中R^0は前記の意味をあらわす)の化合物および
その製薬上許容し得る酸付加塩の製法。 6 一般式 ▲数式、化学式、表等があります▼ (式中R^0はトリフルオロメチルである)であらわさ
れる化合物を活性成分として製薬上許容し得る担体また
は希釈剤と共に包含する人を含む哺乳類の抑うつ症の治
療のための製剤。[Claims] 1. A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^0 is trifluoromethyl) and a pharmaceutically acceptable acid addition salt thereof. 2. The compound of item 1 above, wherein R^0 is trifluoromethyl present at the meta position of the phenyl ring, and a pharmaceutically acceptable acid addition salt thereof. 3. The compound of item 1 above, wherein R^0 is trifluoromethyl present at the para position of the phenyl ring, and a pharmaceutically acceptable acid addition salt thereof. 4. The compound according to any one of items 1 to 3 above in optically pure isomeric form. 5 Reacting a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^0 is trifluoromethyl, and X is selected from halogen and p-toluenesulfonyloxy) with ammonia. A method for producing a compound of the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^0 represents the above meaning) and a pharmaceutically acceptable acid addition salt thereof, characterized by the following. 6. Mammals, including humans, containing a compound represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^0 is trifluoromethyl) as an active ingredient together with a pharmaceutically acceptable carrier or diluent. Preparations for the treatment of depression.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE7509814A SE412384B (en) | 1975-09-04 | 1975-09-04 | ANALOGY PROCEDURE FOR PREPARING ANTIDEPRESSIVE EFFECT TRIFLUORMETHYL SUBSTITUTED ARAL COOLESTERS OF ALANINE |
SE75098145 | 1975-09-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5253831A JPS5253831A (en) | 1977-04-30 |
JPS6013028B2 true JPS6013028B2 (en) | 1985-04-04 |
Family
ID=20325444
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51105451A Expired JPS6013028B2 (en) | 1975-09-04 | 1976-09-04 | Trifluoromethyl-substituted compounds with antidepressant activity |
Country Status (15)
Country | Link |
---|---|
US (1) | US4098901A (en) |
JP (1) | JPS6013028B2 (en) |
AU (1) | AU503030B2 (en) |
BE (1) | BE845805A (en) |
CA (1) | CA1069926A (en) |
CH (1) | CH602585A5 (en) |
DE (1) | DE2638849C2 (en) |
DK (1) | DK146024C (en) |
FI (1) | FI61871C (en) |
FR (1) | FR2322595A2 (en) |
GB (1) | GB1521827A (en) |
IE (1) | IE43424B1 (en) |
LU (1) | LU75713A1 (en) |
NL (1) | NL7609794A (en) |
SE (1) | SE412384B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4846882A (en) * | 1986-01-10 | 1989-07-11 | Fmc Corporation | Herbicidal aryl tetrahydrophthalimides |
IT1201113B (en) * | 1986-01-10 | 1989-01-27 | Fmc Corp | HERBICIDE COMPOUNDS |
IE60455B1 (en) * | 1987-05-27 | 1994-07-13 | Astra Ab | New aralkyl esters and processes for their preparation |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2135641A (en) * | 1936-08-05 | 1938-11-08 | Du Pont | Esters of c-dialkylglycines |
US2480224A (en) * | 1947-03-31 | 1949-08-30 | Searle & Co | Fluorenyl esters and method |
US2543764A (en) * | 1947-07-02 | 1951-03-06 | Searle & Co | Diaralkyl carbinyl esters of dialkylamino alkanoates and the production thereof |
US2625547A (en) * | 1950-01-13 | 1953-01-13 | Sterling Drug Inc | Process of preparing benzhydryl and 9-fluorenyl tertiary aminoalkanoates |
SE394809B (en) * | 1974-03-11 | 1977-07-11 | Astra Laekemedel Ab | ANALOGICAL PROCEDURE FOR THE PREPARATION OF ANTIDEPRESSIVE ACTING ARALKYL ESTERS OF AMINO ACIDS |
-
1975
- 1975-09-04 SE SE7509814A patent/SE412384B/en not_active IP Right Cessation
-
1976
- 1976-08-28 DE DE2638849A patent/DE2638849C2/en not_active Expired
- 1976-08-30 US US05/718,569 patent/US4098901A/en not_active Expired - Lifetime
- 1976-08-31 AU AU17311/76A patent/AU503030B2/en not_active Expired
- 1976-08-31 FI FI762501A patent/FI61871C/en not_active IP Right Cessation
- 1976-09-01 DK DK394876A patent/DK146024C/en not_active IP Right Cessation
- 1976-09-02 NL NL7609794A patent/NL7609794A/en not_active Application Discontinuation
- 1976-09-03 FR FR7626708A patent/FR2322595A2/en active Granted
- 1976-09-03 CA CA260,539A patent/CA1069926A/en not_active Expired
- 1976-09-03 BE BE170306A patent/BE845805A/en not_active IP Right Cessation
- 1976-09-03 LU LU75713A patent/LU75713A1/xx unknown
- 1976-09-03 GB GB36647/76A patent/GB1521827A/en not_active Expired
- 1976-09-03 CH CH1122676A patent/CH602585A5/xx not_active IP Right Cessation
- 1976-09-03 IE IE1965/76A patent/IE43424B1/en unknown
- 1976-09-04 JP JP51105451A patent/JPS6013028B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1521827A (en) | 1978-08-16 |
DE2638849A1 (en) | 1977-03-17 |
IE43424L (en) | 1977-03-04 |
DK146024C (en) | 1983-10-24 |
DE2638849C2 (en) | 1984-08-23 |
SE412384B (en) | 1980-03-03 |
IE43424B1 (en) | 1981-02-25 |
LU75713A1 (en) | 1977-06-15 |
NL7609794A (en) | 1977-03-08 |
FR2322595B2 (en) | 1980-05-09 |
FI61871B (en) | 1982-06-30 |
BE845805A (en) | 1977-03-03 |
FR2322595A2 (en) | 1977-04-01 |
CA1069926A (en) | 1980-01-15 |
FI61871C (en) | 1982-10-11 |
FI762501A (en) | 1977-03-05 |
AU503030B2 (en) | 1979-08-23 |
DK394876A (en) | 1977-03-05 |
JPS5253831A (en) | 1977-04-30 |
US4098901A (en) | 1978-07-04 |
AU1731176A (en) | 1978-03-09 |
SE7509814L (en) | 1977-03-05 |
DK146024B (en) | 1983-05-30 |
CH602585A5 (en) | 1978-07-31 |
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